The proposal is being submitted for review under the R21 (exploratory grant) mechanism. Despite considerable efforts, medications with sound neurobiological rationale have not proven to be consistently effective in the treatment of cocaine dependence (CD). Based on findings from an ongoing study titled 'serotonergic function and treatment outcome in cocaine', the proposed research examines the hypothesis that there are inter-individual differences in neurobiological function, specifically serotonergic (5HT) function, among CD individuals, and that these differences influence the effectiveness of serotonergic pharmacotherapies. In a relatively novel pharmacological approach, the hypothesis will be examined in a 2 X 2 experimental design by randomly assigning 80 CD patients to 12 weeks of double-blind treatment with either paroxetine, a selective serotonergic reuptake inhibitor, or placebo. Subsequently these patients will be divided into lower 5HT and higher 5HT function groups based upon pre-treatment values of platelet tritiated paroxetine binding a measure of serotonin transporter sites and the during treatment and end-of-treatment outcome measures will be compared across the subject groups. The outcome measures will reflect abstinence from drugs and retention in treatment. Also, whether changes in paroxetine binding values during treatment are associated with reduced impulsivity and aggression and with outcome measures will be determined. The data analysis will examine the main effects of medication and 5HT function and then test the Treatment X 5HT interaction that is central to our main hypothesis. The rate of platelet 5HT uptake will also be examined as an additional index of the serotonin transporter. Relationships between this measure and outcome measures will be also explored. The findings may help to better understand the relationships between peripheral measures of 5HT function and clinical and outcome measures among cocaine patients. Moreover, the results may help to improve pharmacological strategies for the treatment of cocaine dependence. [unreadable] [unreadable]